Project Summary/Abstract: For decades, it has been assumed that despite the triggering stimulus, the same brainstem areas are responsible for producing nausea and emesis. However, our recent preliminary studies suggested that nausea and vomiting are complex conditions that include a variety of physiological responses that vary between individuals, and in accordance with the triggering stimulus. This grant uses synergistic approaches to characterize the divergence, convergence, and multisensory integration by brainstem neurons of vestibular and other signals that can produce emesis. Specific Aim 1 includes the first comprehensive comparison of the brainstem pathways that participate in generating nausea and emesis following the intragastric infusion of copper sulfate or presentation of vestibular stimuli to induce motion sickness. By utilizing an innovative statistical approach that we recently developed, we will identify the neural networks that are activated by these stimuli from Fos labeling patterns. We hypothesize that different brainstem networks are engaged in animals that exhibit objective changes in stomach myoelectric activity indicative of nausea following stimulation of vestibular versus gastrointestinal receptors. Specific Aims 2 and 3 respectively use neurophysiologic techniques to characterize the integration of emetic inputs by parabrachial nucleus (PBN) neurons that transmit these signals to supratentorial brain areas, and by parasympathetic preganglionic neurons (PPGNs) in the dorsal motor nucleus of the vagus (DMV) and near-by nucleus ambiguus that transmit the signals to peripheral effectors. Aim 3 will also compare the responses of PPGNs to those of neurons in two adjacent areas that play a key role in integrating these signals: nucleus tractus solitarii (NTS) and the lateral tegmental field (LTF), which comprises the brainstem ?vomiting center.? Aim 3 incorporates the first characterization of responses to vestibular stimulation of PPGNs; although these neurons coordinate the changes in gastrointestinal activity during vomiting, virtually nothing is known about modifications in their firing rate elicited by emetic stimuli. By contrasting the integration of inputs from vestibular and gastrointestinal afferents in these key groups of brainstem neurons (PPGNs and those in PBN, NTS, and LTF), we can test our overall hypothesis that signals that elicit vomiting are processed independently in the brainstem, and only converge on neurons that directly control emetic responses. Understanding how vestibular and gastrointestinal signals are transformed in brainstem emetic pathways is key to generating insights into new treatments for nausea and vomiting. At the conclusion of the proposed studies, we will have identified brainstem networks that mediate nausea and vomiting, the influences of nausea-related and emetic signals on the activity of neurons in those networks, and their differential and/or synergistic responsiveness to vestibular and gastrointestinal signals.